We will study the hemodynamic and pathophysiologic effects of long-term extra-corporeal perfusion with a membrane lung on the normal and acutely injured pulmonary circulation. Advances in the technology of safe, long-term bypass have rapidly outstripped our understanding of the effects of this powerful technique on the lung. Indeed, although the patient with severe acute lung injury can be stabilized by perfusion for one or two weeks without hypoxemia or hypercapnea, the injured lung generally fails to repair. We need to answer basic questions such as: What is the effect of altered cardiac output on lung function and how does bypass influence the pathophysiology of acute respiratory failure? We therefore plan to study the effects of bypass on the pulmonary circulation of sheep and baboons with acutely induced lung injury and on selected potentially reversible clinical cases of severe adult respiratory distress syndrome. Novel direct lung therapies including lavage with anti-inflammatory and antifibrotic solutions will be studied. Despite therapy, the lung is often destroyed by severe acute respiratory failure. For these patients, a possible future therapy is chronic partial perfusion with a low blood flow resistance membrane artificial lung. Such a device can reduce pulmonary hypertension as well as assist gas exchange. We plan to continue to develop and test advanced biomaterials capable of prolonged gas exchange, high efficiency oxygenators, chronic animal models of pulmonary artery to left atrial bypass, and central cannulation techniques. Eventually, such efforts may provide a pathway to a chronic extracorporeal gas exchanging prosthesis driven directly by the right ventricle.